Study of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Advanced Solid Malignancies (FAK-PD1)

A Phase I/IIA Study to Assess Safety, Tolerability and Preliminary Activity of the Combination of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Patients With Advanced Solid Malignancies (FAK-PD1)

This study will explore whether defactinib (a FAK inhibitor) can be safely and tolerably combined with pembrolizumab (a PD-1 inhibitor) and will look for early indications of improved anticancer immunotherapy. It will focus on three key cancers, all in clear need of improved therapies - NSCLC, pancreatic cancer and mesothelioma.

Study Overview

• Status: Unknown
• Conditions: Pancreatic Neoplasms; Mesothelioma; Carcinoma, Non-small-cell Lung
• Intervention / Treatment: Drug: Defactinib; Drug: Pembrolizumab

Detailed Description

Programmed cell death receptor 1 (PD-1) blockade is a well-tolerated novel cancer immunotherapy with monotherapy response rates of 20-50% in tumour types such as bladder, melanoma, renal and non-small cell lung cancer (NSCLC), along with durable benefit. However, other tumour types (such as pancreatic cancer) have been poorly responsive and it is likely that the activity of PD-1 blockade is limited in many patients by the presence of additional immunosuppressive tumour microenvironment interactions. The investigators have recently shown in preclinical studies that Focal Adhesion Kinase (FAK) inhibition can re-model multiple aspects of the tumour immune microenvironment, shifting the balance from inhibitory Tregs, TAMs, CAFs & MDSCs, to one which supports an active CD8+ T cell adaptive immune response, suitable for synergistic anti-PD-1 therapy.

The current clinical study will explore whether FAK inhibition (defactinib/VS-6063) can be safely and tolerably combined with PD-1 blockade (pembrolizumab), with early indications of improved anticancer immunotherapy from this novel combination. The investigators will focus on three key tumour types, all cancers in clear need of improved therapies. NSCLC, aiming to augment the moderate monotherapy activity of PD-1 blockade; pancreatic cancer, aiming to release immunological activity in this otherwise resistant cancer; and, finally, mesothelioma, where emerging data suggests both agents may have monotherapy activity, including a potential additional mode of action via synthetic lethality of FAK inhibition in the ~50% of mesothelioma with NF2 mutation.

Phase I/IIa clinical study of defactinib (VS-6063, FAK inhibitor) in combination with pembrolizumab (anti-PD-1) therapy, initially in an "all-comers" dose escalation phase, and subsequently in expansion cohorts at the optimal doses in patients with: (a) pancreatic cancer; (b) NSCLC; and (c) mesothelioma. Safety, tolerability and clinical activity will be explored, as well as extensive translational work to characterise the biological effects and explore potential predictive and pharmacodynamic biomarkers.

PHASE I

Dose-escalation in an "all-comers" phase I population, with treatment-refractory advanced solid malignancies, unselected by tumour type as follows:

Cohorts 200 mg (IV) pembrolizumab every 3 weeks: plus 200 mg (oral) defactinib twice daily 200 mg (IV)pembrolizumab every 3 weeks: plus 400 mg (oral) defactinib twice daily

PHASE II

Expansions in pancreatic ductal adenocarcinoma, non-small cell lung cancer & mesothelioma (each 15-16 evaluable patients).

Pancreatic

Pancreatic expansion for response assessment (single arm). Optional paired biopsies prior to treatment and after 14 days of treatment. Concurrent therapy with pembrolizumab + defactinib (VS-6063) from the start (c.f. NSCLC & mesothelioma expansions below). 15 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 6.

• Classic "stromal" cancer, where the tumour microenvironment is believed to limit the activity of multiple agents. However broad preclinical data for various approaches to re-modelling the tumour microenvironment to permit immunotherapy.
• Minimal single-agent anti-PD-1/PD-L1 activity, explores hypothesis of conversion to sensitivity and predictive biomarkers for this.

NSCLC

NSCLC paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and after around 14 days of treatment. 1:1 randomised split of patients having their on-treatment biopsy after concurrent therapy, or after a defactinib (VS-6063) monotherapy run-in. 16 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 11.

• Moderate single-agent anti-PD-1/PD-L1 activity explores hypothesis of amplification of sensitivity and predictive biomarkers for this.
• Paired-biopsy assessment of proof of mechanism biomarkers (FAK signalling, tumour immune microenvironment).

Mesothelioma

Mesothelioma paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and after around 14 days of treatment. 1:1 randomised split of patients having their on-treatment biopsy after concurrent therapy, or after a defactinib (VS-6063) monotherapy run-in). 16 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 11.

• Emerging single-agent immune checkpoint, as well as potential FAK-inhibitor activity, explores hypothesis of multi-modal combination activity (microenvironment, checkpoint and synthetic lethality), as well as predictive biomarkers for this.
• Paired-biopsy assessment of proof of mechanism biomarkers (FAK signalling, tumour immune microenvironment).

• Study Type: Interventional
• Enrollment (Anticipated): 59
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Dawn Currie; Phone Number: 00 44 141 301 7194; Email: dawn.currie@glasgow.ac.uk

Study Locations

• United Kingdom
  • Belfast, United Kingdom, BT9 7BL
    • Recruiting
    • Belfast Health and Social Care Trust, Cancer Centre, Lisburn Road
    • Contact: Melanie Morris; Email: melanie.morris@belfasttrust.hscni.net
    • Principal Investigator: Vicky Coyle, Dr
  • Edinburgh, United Kingdom, EH4 2XR
    • Recruiting
    • Edinburgh Cancer Research Centre, Western General Hospital
    • Contact: Olga Demyanov; Email: olga.demyanov@ed.ac.uk
  • Glasgow, United Kingdom, G12 0YN
    • Recruiting
    • Beatson West of Scotland Cancer Centre
    • Contact: Jeff Evans; Email: j.evans@beatson.gla.ac.uk
    • Principal Investigator: Jeff Evans, Prof
  • Leicester, United Kingdom, LE2 7LX
    • Recruiting
    • Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary
    • Contact: Dean Fennell; Email: df132@leicester.ac.uk
    • Principal Investigator: Dean Fennell, Prof
  • Southampton, United Kingdom, SO16 6YD
    • Recruiting
    • Cancer Research UK Centre, Southampton University Hospitals and University of Southampton
    • Contact: Christian Ottensmeier; Email: c.h.ottensmeier@soton.ac.uk
    • Principal Investigator: Christian Ottensmeier, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All Patients:

• Informed, written consent
• Male or female, aged 18 years or older at the time consent is given
• ECOG performance status 0 or 1, with no deterioration over the previous 2 weeks
• Life expectancy of at least 3 months
• Measurable disease according to irRECIST criteria, with at least one measurable lesion that has objectively progressed since (or on) any previous therapy
• Adequate bone marrow, liver and renal function on blood investigations within 7 days prior to treatment initiation
• Patients must have been offered all appropriate standard-of-care treatments (or all those indicated before anti-PD-1/PD-L1 therapy, if licensed)
• Patients must agree to use adequate contraceptive measures for the course of the study through 120 days after the last dose of study medication
• Women of child-bearing potential must have a negative pregnancy test within 72 hours prior to start of dosing
• Consent to supply any available archival tissue

Dose escalation (Phase I):

• Pathological diagnosis of any advanced solid tumour type, with confirmation that a tissue sample (core biopsy or resected specimen) is available

Pancreatic expansion (Phase IIa):

• Pathological diagnosis of pancreatic ductal adenocarcinoma with confirmation that a tissue sample (core biopsy or resected specimen) is available

NSCLC expansion (Phase IIa):

• Pathological diagnosis of non-small cell lung cancer (NSCLC)
• Lesion suitable for repeat biopsy
• Baseline biopsy containing tumour material during eligibility
• Consent for paired biopsies on study

Mesothelioma expansion (Phase IIa):

• Pathological diagnosis of mesothelioma
• Lesion suitable for repeat biopsy
• Baseline biopsy containing tumour material during eligibility
• Consent for paired biopsies on study

Exclusion Criteria:

All patients:

• An additional invasive cancer in the last 5 years (other than treated and controlled localised non-melanoma skin cancer or cervical carcinoma-in-situ, or indolent prostate cancer that has been stable for > 1 year)
• Any central nervous system metastases unless treated and asymptomatic, as well as stable on imaging and not requiring steroids in the preceding 4 weeks
• Any interventional studies, systemic cancer therapies or monoclonal antibodies in the preceding 4 weeks (6 weeks for mitomycin C and nitrosureas)
• Any live vaccines in the preceding 4 weeks
• Systemic immunosuppressive agents in the preceding 2 weeks. Immunosuppressive agents include steroids such as prednisolone (doses ≥ 15 mg daily) or dexamethasone (doses ≥ 2 mg daily).

Replacement therapy (e.g. physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc) is not considered a form of systemic treatment

• Diagnosis of immunodeficiency
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Known interstitial lung disease or active, non-infectious pneumonitis
• Known history of Tuberculosis (TB), Human Immunodeficiency Virus (HIV) or active Hepatitis B or C
• Other severe or uncontrolled systemic diseases (e.g. uncontrolled hypertension, recent myocardial infarction, organ failure or active infection)
• Residual (non-laboratory) toxicities greater than grade 1 (CTCAE v4.03) from previous therapies despite optimal supportive therapy, including fatigue, anorexia, nausea or diarrhoea, but with the exception of alopecia
• Pregnancy or lactation
• Limited ability to swallow or absorb oral medications
• Hypersensitivity to defactinib (VS-6063), pembrolizumab or excipients (including L-histidine, L-histidine hydrochloride monohydrate, sucrose or polysorbate 80)
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Previous treatment with an anti-PD-1 or anti-PDL1 agent
• Previous severe or life-threatening skin adverse reaction with other immune-stimulatory anticancer agents
• Current solid organ transplant recipient

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose - escalation; Does-escalation in an "all-comers" phase I population, with treatment-refractory advanced solid malignancies, unselected by tumour type. Two cohorts of up to evaluable 6 patients in each: Cohort 1: 200mg (IV) pembrolizumab every 3 weeks; plus 200mg (oral) defactinib twice daily; Cohort 2: 200mg (IV) pembrolizumab every 3 weeks; plus 400mg (oral) defactinib twice daily Interventions: Drug: Defactinib; Drug: Pembrolizumab	Drug: Defactinib; cross reference with arm/group descriptions; Other Names: VS-6063; Drug: Pembrolizumab; cross reference with arm/group descriptions; Other Names: Keytruda and MK-3475
Experimental: Pancreatic; Pancreatic expansion for response assessment (single arm). Optional paired biopsies prior to treatment and after 14 days of treatment. All would have concurrent therapy with pembrolizumab + defactinib (VS-6063) from the start (c.f. NSCLC & mesothelioma expansions below). 15 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 6	Drug: Defactinib; cross reference with arm/group descriptions; Other Names: VS-6063; Drug: Pembrolizumab; cross reference with arm/group descriptions; Other Names: Keytruda and MK-3475
Experimental: NSCLC; NSCLC paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and after around 14 days of treatment. 1:1 randomised split of patients having their mandatory on-treatment biopsy after concurrent therapy, or after a defactinib (VS-6063) monotherapy run-in. 16 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 11.	Drug: Defactinib; cross reference with arm/group descriptions; Other Names: VS-6063; Drug: Pembrolizumab; cross reference with arm/group descriptions; Other Names: Keytruda and MK-3475
Experimental: Mesothelioma; Mesothelioma paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and around 14 days of treatment. 1:1 randomised split of patients having thier on-treatment biopsy after concurrent therapy, or after defactinib (VS-6063) monotherapy run-in. 16 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 11.	Drug: Defactinib; cross reference with arm/group descriptions; Other Names: VS-6063; Drug: Pembrolizumab; cross reference with arm/group descriptions; Other Names: Keytruda and MK-3475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events (AEs) using CTCAE v4.03 (to determine dose limiting toxicities (DLTs) and maximum tolerated dose (MTD))	Evaluate the tolerability profile and optimal dose of defactinib in combination with pembrolizumab, using CTCAE v4.03 Adverse Event recording.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR), using best objective response by irRECIST	Evaluate the response rate, by irRECIST, of the combination of defactinib and pembrolizumab in patients with advanced solid malignancies.	3 years
Duration of response (DoR)	Evaluate the duration of responses, by irRECIST, of the combination of defactinib and pembrolizumab in patients with advanced solid malignancies. Duration will be measured from the first scan showing radiological response (CR or PR), until (irRECIST confirmed) progression.	3 years
Progression free survival (PFS)	Evaluate progression free survival of the combination of defactinib and pembrolizumab in patients with advanced solid malignancies. Duration will be measured from enrolment, until (irRECIST confirmed) progression.	3 years
Change in FAK Y397 phosphorylation	change in FAK Y397 phosphorylation between baseline biopsy and a repeat biopsy afer 2 weeks of therapy	2 weeks
Change in immune cell infiltrate	change in immune cell infiltrate between baseline biopsy and a repeat biopsy after 2 weeks of therapy	2 weeks

Collaborators and Investigators

• Sponsor: NHS Greater Glasgow and Clyde
• Collaborators: Merck Sharp & Dohme LLC; Cancer Research UK; University of Southampton; Queen's University, Belfast; University of Edinburgh; Verastem, Inc.; University of Leicester; University of Glasgow
• Investigators: Principal Investigator: Stefan Symeonides, Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR; Principal Investigator: Jeff Evans, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN; Principal Investigator: Christian Ottensmeier, Cancer Research UK Centre, Southampton University Hospitals and University of Southampton, Southampton SO16 6YD; Principal Investigator: Dean Fennell, Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX; Principal Investigator: Vicky Coyle, Belfast Health and Social Care Trust, Cancer Centre, Lisburn Road, Belfast BT9 7BL

Study record dates

Study Major Dates

• Study Start (Actual): July 4, 2017
• Primary Completion (Anticipated): May 1, 2019
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: April 20, 2016
• First Submitted That Met QC Criteria: April 28, 2016
• First Posted (Estimate): May 2, 2016

Study Record Updates

• Last Update Posted (Actual): March 19, 2018
• Last Update Submitted That Met QC Criteria: March 16, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Pancreatic Diseases; Adenoma; Neoplasms, Mesothelial; Carcinoma, Non-Small-Cell Lung; Pancreatic Neoplasms; Mesothelioma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: GN15ON133; 2015-003928-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No